非小细胞肺癌PD-1PD-L1表达与EGFR基因突变临床特征及预后的相关性

目的探讨非小细胞肺癌患者肺组织中程序性死亡受体-1、程序性死亡配体-1蛋白表达与表皮生长因子受体基因突变、临床特征及预后的相关性,为临床治疗提供参考.方法将117例非小细胞肺癌患者设为研究组,60例良性病例设为对照组,采用免疫组化法检测两组肺组织中程序性死亡受体-1、程序性死亡配体-1蛋白表达,采用荧光聚合酶链式反应法检测研究组表皮生长因子受体基因突变情况,对研究组不同临床特征患者的表皮生长因子受体基因突变及程序性死亡受体-1、程序性死亡配体-1蛋白表达进行分析.结果研究组肺组织中程序性死亡受体-1、程序性死亡配体-1蛋白阳性表达率(35.0%、54.7%)显著高于对照组(19.0%、15.5%)(P<0.05或0.01);研究组女性、高分化患者表皮生长因子受体基因突变率高,肿瘤分期Ⅲ期、Ⅳ期患者程序性死亡配体-1蛋白表达阳性率高,程序性死亡配体-1蛋白表达与表皮生长因子受体基因突变呈显著正相关,程序性死亡配体-1蛋白表达阳性较阴性患者的无进展生存期显著缩短(P<0.05或0.01).结论非小细胞肺癌患者肺组织中程序性死亡受体-1、程序性死亡配体-1蛋白表达阳性率高,程序性死亡配体-1蛋白表达与表皮生长因子受体基因突变显著相关;对表皮生长因子受体基因突变型非小细胞肺癌患者使用表皮生长因子受体的酪氨酸激酶抑制剂治疗,程序性死亡配体-1蛋白表达阳性患者可能预后较差.     

Tissue expression of PD-L1 mediates peripheral T cell tolerance

Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in inhibiting interleukin-2 and interferon-gamma production during T cell activation. However, PD-L1 has a unique and critical role in controlling self-reactive T cells in the pancreas. Our studies with bone marrow chimeras demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is insufficient to prevent the early onset diabetes that develops in PD-L1/PD-L2(-/-) non-obese diabetic mice. PD-L1 expression in islets protects against immunopathology after transplantation of syngeneic islets into diabetic recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell-mediated tissue destruction and effector cytokine production. These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1-PD-L1 interactions in mediating tissue tolerance.     

倾向性评分匹配分析口咽癌PD-L1的表达与HPV感染及预后的相关性研究

目的探讨口咽鳞癌中程序性细胞死亡配体1(PD-L1)与HPV感染状态及患者预后的相关性。方法采用倾向性评分匹配,纳入HPV阳性及HPV阴性口咽癌各50例,对患者进行长期随访,通过免疫荧光检测PD-L1的表达,分析其与HPV感染状态及临床预后的相关性。结果 HPV阳性组及HPV阴性组5年总生存率分别为66%和40%(P=0.003),5年疾病特异性生存率分别为73%和44%(P=0.001)。PD-L1表达率在HPV阳性组较HPV阴性组明显升高(70%vs 42%,P=0.005)。PD-L1与除年龄(P=0.020)外的其他临床病理特征无明显相关性,PDL1阳性为口咽癌独立良好预后因素(DSS,P<0.001;OS,P<0.001)。进一步预后分析提示HPV+/PD-L1+患者较HPV+/PD-L1-者(DSS,P<0.001;OS,P=0.004),HPV-/PD-L1+者(DSS,P=0.010;OS,P=0.047)以及HPV-/PD-L1-者(DSS,P<0.001;OS,P<0.001)具有显著的预后优势。结论 HPV阳性口咽癌患者预后较好,PD-L1在HPV阳性口咽癌中的表达升高,PD-L1阳性可能与HPV阳性口咽癌患者较好的临床预后相关。     

过敏性紫癜患儿急性期外周血PD-1和PD-L1的表达及研究

【目的】探讨过敏性紫癜患儿急性期外周血程序性死亡因子-1（programmed death-1,PD-1）以及其主要配体（programmed death-1 ligand,PD-L1）的表达及其意义。【方法】采用荧光抗体染色技术经流式细胞仪检测40例过敏性紫癜患儿急性期（观察组）和20例健康儿童（对照组）外周血单核细胞和淋巴细胞上的PI）_1和PD-L1阳性表达率,同时比较过敏性紫癜患儿伴或不伴有肾炎之间的差异。【结果】过敏性紫癜患儿急性期外周血单核细胞上的PD-1和PD-L1阳性表达率低于对照组（P〈0．05）,而观察组和对照组淋巴细胞上的PD-1和PD-L1的表达差异无统计学意义（P〉0．05）。同时,紫癜性肾炎患儿和非紫癜性肾炎组患儿之间PD-1和PD-L1在单核细胞上的阳性表达率差异也无统计学意义（P〉0．05）,而紫癜性。肾炎组患儿的PD-1和PD-L1在淋巴细胞上的阳性表达率均显著大于非紫疯性肾炎组（P〈0．05）。【结论】过敏性紫癜患儿急性期外周血单核细胞上的PD-1和PD-L1阳性表达率下降,而紫癜性肾炎患儿相对非紫癜性肾炎组患儿PD1在淋巴细胞上阳性表达率上降,存在免疫调节机制紊乱,PD-1和PD-L1在过敏性紫癜患儿急性期发病机制中发挥一定作用。     

口腔鳞状细胞癌中PD-L1的表达与P16、HPV感染以及淋巴结转移关系分析

目的观察口腔鳞状细胞癌中程序性死亡分子-L1配体(PD-L1)的表达与乳头瘤病毒-16 (P16)、人乳头瘤病毒(HPV)感染以及淋巴结转移关系,初步探讨PD-L1在口腔鳞状细胞癌病情发展中的作用。方法以本院2017年6月至2018年6月期间收集到的口腔鳞状细胞癌组织蜡块为研究标本,行采用免疫组化染色法检测组织标本PD-L1、P16及HPV表达情况。观察PD-L1、P16、HPV的表达情况,并采用Spearman等级相关性分析法分析PD-L1与P16、HPV感染以及淋巴结转移关系的相关性。结果 51例口腔鳞状细胞癌组织中,PD-L1呈阳性表达44例(86.27%),PD-L1呈阴性表达7例(13.72%),P16呈阳性表达22例(43.14%),P16呈阴性表达29例(56.86%)。口腔鳞状细胞癌组织中的PD-L1表达与P16表达呈负相关(rs=-0.819,P=0.000),与淋巴结转移分期之间呈负相关(rs=-0.736,P=0.000),与HPV感染呈正相关(rs=0.653,P=0.000)。结论 PD-L1在口腔鳞状细胞癌组织中呈高度表达,且与口腔鳞状细胞癌病情发展标志物P16、HPV密切相关,同时在淋巴结转移中也具有促进作用,因此,深入研究PD-L1在口腔鳞状细胞癌病情发展的作用,有助于口腔鳞状细胞癌免疫疗法的完善。     

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1^–/– donors. PD-L1–deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1^–/– donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell–mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.     

PD-L1和miR-34a在三阴乳腺癌中的表达及相关性研究

目的探讨PD-L1和miR-34a在三阴乳腺癌(TNBC)中的表达、相关性及临床意义。方法选取三阴乳腺癌组织和癌旁组织标本各40例,RT-PCR检测miR-34a的相对表达量,免疫组化法检测PD-L1的表达,并进行统计学分析。结果PD-L1在TNBC细胞中有13例阳性(32.5%),表达阳性率高于癌旁组织(0),差异显著(P<0.05);miR-34a在TNBC细胞中的表达量是癌旁组织中的0.58倍(0.546±0.083 vs 0.940±0.097),差异显著(P<0.05);并且,miR-34a和PD-L1的表达呈负相关性(r=-0.403,P<0.05)。结论PD-L1在TNBC细胞中的表达阳性率高,miR-34a低,且miR-34a与PD-L1的表达呈负相关性,提示在TNBC中,miR-34a可能参与调控PD-L1的免疫应答反应。     

PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice

The inhibitory receptor programmed death 1 (PD-1) is upregulated on antigen-specific CD8⁺ T cells during persistent viral infections. Interaction with PD-1 ligand 1 (PD-L1) contributes to functional exhaustion of responding T cells and may limit immunopathology during infection. PD-L1 is expressed on both hematopoietic and nonhematopoietic cells in tissues. However, the exact roles of PD-L1 on hematopoietic versus nonhematopoietic cells in modulating immune responses are unclear. Here we used bone marrow chimeric mice to examine the effects of PD-L1 deficiency in hematopoietic or nonhematopoietic cells during lymphocytic choriomeningitis virus clone 13 (LCMV CL-13) infection. We found that PD-L1 expression on hematopoietic cells inhibited CD8⁺ T cell numbers and function after LCMV CL-13 infection. In contrast, PD-L1 expression on nonhematopoietic cells limited viral clearance and immunopathology in infected tissues. Together, these data demonstrate that there are distinct roles for PD-L1 on hematopoietic and nonhematopoietic cells in regulating CD8⁺ T cell responses and viral clearance during chronic viral infection.     

PD-L1和PD-1在非小细胞肺癌中的表达及其临床意义

目的:探讨PD-L1和PD-1在非小细胞肺癌(NSCLC)中的表达及其与患者临床病理参数、预后的相关性。方法:收集47例NSCLC标本,运用免疫组化方法检测NSCLC中PD-L1和PD-1的表达,分析其与患者各项临床指标及预后的关系。结果:PD-L1在癌细胞及癌间质淋巴细胞和巨噬细胞的表达阳性率分别为48.93%(23/47)和61.70%(29/47),两者表达水平与肿瘤临床分期及淋巴结转移呈正相关(P<0.05),与患者预后呈负相关(P<0.05)。PD-1蛋白主要定位在癌间质淋巴细胞,PD-1+淋巴细胞数量与PD-L1蛋白在癌细胞及癌间质的表达均呈正相关(P<0.05)。结论:PD-L1与NSCLC分期、淋巴结转移、PD-1阳性淋巴细胞及预后密切相关。     

PD-L1、CPEB4和GRP在脑胶质瘤中的表达及与临床病理特征和预后的关系研究

目的分析程序性死亡受体-配体1(PD-L1)、胞质多聚腺苷酸化成分结合蛋白4(CPEB4)、胃泌素释放肽(GRP)在脑胶质瘤中的表达及与临床病理特征和预后的关系。方法回顾性选取辽宁省健康产业集团铁煤总医院2015年2月至2018年11月收治的94例脑胶质瘤患者取手术切除的癌组织作为脑胶质瘤组(94例)同时取距离肿瘤组织5 mm处的组织作为癌旁组(94例),另取同期颅脑损伤减压术切除的脑组织作为正常对照组(87例)。采用免疫组化法检测三组PD-L1、CPEB4、GRP表达情况;分析PD-L1、CPEB4、GRP在脑胶质瘤患者不同临床病理特征中的表达差异,并比较预后良好组和预后不良组临床病理特征脑胶质瘤组织中PD-L1、CPEB4、GRP表达;通过Logistic回归分析PD-L1、CPEB4、GRP对预后的影响。结果脑胶质瘤组患者组织中PD-L1、CPEB4、GRP强阳性及阳性表达率高于癌旁组、正常对照组差异有统计学意义(P <0.05)。脑胶质瘤组织中PD-L1、CPEB4、GRP在WHO分级Ⅲ~Ⅳ级中阳性率高于Ⅰ~Ⅱ级在KPS评分<80分患者中阳性率高于KPS评分≥80分患者差异有统计学意义(P<0.05)。患者随访1~3年,出现复发者16例(17.02%),肿瘤源性死亡4例(4.26%),预后不良共20例(21.28%)。预后不良组患者PD-L1、CPEB4、GRP阳性表达率高于预后良好组差异有统计学意义(P <0.05)。多因素Logistic回归分析结果显示,PD-L1、CPEB4、GRP阳性是脑胶质瘤患者预后不良的危险因素(B=2.535、2.164、2.373,95%CI=1.513~105.257、1.764~42.973、1.274~90.311,均P<0.05)。结论 PD-L1、CPEB4、GRP在脑胶质瘤组织中阳性表达率增高且与WHO分级、KPS评分有关,并影响患者预后,检测PD-L1、CPEB4、GRP对脑胶质瘤患者的病理分级和预后评估具有重要意义。     

Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients

Introduction  

Studies on the role of programmed death-1(PD-1) and its main ligand (PD-L1) during experimental models of sepsis have shown that the PD-1/PD-L1 pathway plays a pathologic role in altering microbial clearance, the innate inflammatory response and accelerated apoptosis in sepsis. However, the expression of PD-1 and PD-L1 and their role during the development of immune suppression in septic patients have not been elucidated. The present study was designed to determine whether the expression of PD-1 and PD-L1 is upregulated in septic shock patients and to explore the role of this pathway in sepsis-induced immunosuppression.     

PD-1/PD-L1 antagonists in gastric cancer: Current studies and perspectives

Immune checkpoints release suppressive signals for T cells, which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors. At present, programmed death receptor 1 (PD-1)/programmed death ligand-1 (PD-L1) has become the most promising therapeutic target. PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers, such as melanoma and non-small-cell lung cancer. Moreover, PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer, and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool. Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer. Furthermore, there are many molecules involved in the regulation of PD-1/PD-L1 expression, and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer. In this review, the efficacy, safety, and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.     

临床、病理、MRI特征及IVIM参数联合模型预测宫颈癌程序性细胞死亡蛋白1及其配体(PD-1/PD-L1)表达

目的 基于SHAP法观察以临床、病理、MRI特征及体素内不相干运动（IVIM）成像定量参数联合模型预测宫颈癌细胞程序性死亡蛋白1（PD-1）及其配体（PD-L1）表达的价值。方法 采集63例治疗前初诊宫颈癌盆腔MRI，并对病理标本行PD-1/PD-L1免疫组织化学染色；比较PD-1表达阳性与阴性组、PD-L1表达阳性与阴性组临床、病理、MRI表现及IVIM参数（真实弥散系数D、灌注相关弥散系数D^*及灌注分数f）的差异，并以logistic回归分析筛选宫颈癌PD-1及PD-L1表达阳性的独立影响因素，建立预测宫颈癌PD-1及PD-L1表达阳性联合模型；以受试者工作特征（ROC）曲线评估模型诊断效能，以SHAP法解释其中各变量的贡献价值。结果 PD-1阳性组与阴性组、PD-L1阳性组与阴性组之间肿瘤病理分级、宫旁浸润、淋巴结转移及D值差异均有统计学意义（P均<0.05）。FIGO分期、肿瘤病理分级、宫旁浸润、淋巴结转移和D值均为宫颈癌PD-1/PD-L1表达阳性的独立影响因素（P均<0.05）；以之建立的联合模型的曲线下面积分别为0.85及0.89。根据SHAP值，联合模型中FIGO分期和肿瘤病理分级的贡献最大。结论 以宫颈癌临床、病理、MRI特征及IVIM参数D值构建的联合模型可有效预测其PD-1/PD-L1表达。     

细胞程序性死亡-配体1基因启动子区rs10815225多态性与结直肠癌的关联研究

目的探讨位于细胞程序性死亡-配体1(PD-L1)基因启动子区的rs10815225多态性与结直肠癌的相关性。方法直接测序法分析215例结直肠癌患者和236例体检健康者rs10815225多态性,定量PCR检测65例结直肠癌组织中PD-L1 mRNA的表达变化。结果与GG基因型相比,CG基因型显著降低了结直肠癌的发病风险(OR=0.48,95%CI 0.28~0.83,P=0.01)。双荧光素酶报告基因结果显示,与rs10815225G等位基因相比,rs10815225C对应的荧光素酶活性显著降低(P<0.05)。基因型—表型结果显示,携带rs10815225CG基因型结直肠癌患者中PD-L1 mRNA表达明显低于GG基因型携带者(P<0.05)。结论PD-L1基因启动子区rs10815225CG基因型可能通过降低基因转录活性和PD-L1 mRNA表达,从而降低中国汉族人群结直肠癌的发病风险。     

The Clinical Relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 Network in Chemoresistant Non-small-cell Lung Cancer

Programmed cell death ligand-1 (PD-L1) has recently gained considerable attention for its role in tumor immune escape. Here, we identify a miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer (NSCLC), independent of immunoinhibitory signals. miR-197 is downregulated in platinum-resistant NSCLC specimens, resulting in the promotion of chemoresistance, tumorigenicity, and pulmonary metastasis in vitro and in vivo. Mechanistic investigations reveal that a miR-197-mediated CKS1B/STAT3 axis exerts tumor progression regulated by various oncogenic genes (Bcl-2, c-Myc, and cyclin D1), and PD-L1 is a putative biomarker of this axis. Furthermore, we demonstrate that a miR-197 mimic sensitizes PD-L1^high drug-resistant cells to chemotherapy. These results indicate that the biological interaction between PD-L1 and chemoresistance occurs through the microRNA regulatory cascade. More importantly, expression levels of miR-197 are inversely correlated with PD-L1 expression (n = 177; P = 0.026) and are associated with worse overall survival (P = 0.015). Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.     

血液透析和肾移植患者外周血淋巴细胞PD-L1的表达

目的:探讨PD-L1在血液透析和肾移植患者外周血淋巴细胞上的表达及意义.方法:选取2011年1月至2011年9月在我院住院的24例维持性血液透析患者、18例正常肾移植受者作为两个病例组,另外选择10例健康志愿者作为正常对照组.采集三组人群的外周血,运用流式细胞染色技术检测淋巴细胞PD-L1的表达情况.结果:维持性血液透析组淋巴细胞群中CD3+PD-L1+比例明显高于正常肾移植受者组(P＜0.05)和正常对照组(P＜ 0.001),且正常肾移植受者组亦高于正常对照组(P＜0.05).而淋巴细胞群中CD3-PD-L1+比例在维持性血液透析组和正常肾移植受者组中表达均高于正常对照组(P＜ 0.001和P＜0.05),但维持性血液透析组与正常肾移植受者组之间无统计学差异(P＞0.05).结论:PD-L1在血液透析和肾移植患者外周血淋巴细胞中表达上调,其可能参与了血液透析患者免疫功能低下状态的形成及正常肾移植受者免疫耐受的维持.     

PD-L1阻断对慢性髓系白血病源性树突状细胞的功能影响

程序性死亡-1配体-1(PD-L1)作为近年来发现的B7家族新的成员,已被证实有免疫负调节作用,白血病源性树突状细胞(DC)高表达PD-L1可能是影响其功能的原因之一,本研究试图阻断PD-L1在DC上的表达以增强白血病源性DC的免疫刺激功能。应用人rhGM-CSF、rhIL-4及TNF-α细胞因子组合诱导慢性髓系白血病细胞(CML)分化DC,观察给予加或不加PD-L1单克隆抗体对DC的影响。应用流式细胞术检测DC免疫表型及PD-L1,MTT法检测DC刺激自体T淋巴细胞的增殖能力,ELISA法测定上清液中IFN-γ、IL-2和IL-10的水平。结果显示,负性调节分子PD-L1随着慢性髓系白血病源性树突状细胞(CML-DC)成熟表达不断升高,阻断PD-L1能增强CML-DC刺激自体T淋巴细胞增殖的能力,促进T细胞分泌IFN-γ和IL-2并抑制IL-10的产生(p<0.05)。结论:阻断PD-L1可增强白血病源性DC的功能,为白血病DC瘤苗治疗技术提供了新的方法。     

CHI3L1 regulates PD-L1 and anti–CHI3L1–PD-1 antibody elicits synergistic antitumor responses

Evasion of the immune response is a hallmark of cancer, and programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) are major mediators of this immunosuppression. Chitinase 3–like 1 (CHI3L1) is induced in many cancers, where it portends a poor prognosis and contributes to tumor metastasis and spread. However, the mechanism(s) that CHI3L1 uses in metastasis have not been defined. Here we demonstrate that CHI3L1 regulates the expression of PD-L1, PD-L2, PD-1, LAG3, and TIM3 and plays a critical role in melanoma progression and lymphatic spread. CHI3L1 also contributed to IFN-γ–stimulated macrophage PD-L1 expression, and RIG-like helicase innate immunity suppressed CHI3L1, PD-L1, and melanoma progression. Individual antibodies against CHI3L1 or PD-1 had discrete antitumor effects and additive antitumor responses in metastasis models and T cell–tumor cell cocultures when administered simultaneously. Synergistic cytotoxic tumor cell death was seen in T cell–tumor cell cocultures, and significantly enhanced antitumor responses were seen in in vivo tumor models treated with bispecific antibodies that simultaneously target CHI3L1 and PD-1. CHI3L1 contributes to tumor progression by stimulating the PD-1/PD-L1 axis and other checkpoint molecules. The simultaneous targeting of CHI3L1 and the PD-1/PD-L1 axis with individual and, more powerfully, with bispecific antibodies represents a promising therapy for pulmonary metastasis and progression.     

MSI、PD-L1在NSCLC患者中的表达及其与预后的相关性

目的探讨微卫星不稳定性(MSI)、程序性死亡配体-1(PD-L1)在非小细胞肺癌(NSCLC)患者中的表达水平及其预后相关性。方法收集2010年6月至2014年12月在本院收集的86例NSCLC患者手术切除癌组织及对应距病灶5 cm以上癌旁正常组织。利用PCR技术检测172例样品中BAT-25、BAT-26、D2S123、D5S346、D17S250五个位点的MSI,判断MSI表达情况。采用免疫组化法检测PD-L1的水平。对MSI、PD-L1与临床病理因素的关系进行分析,所有患者根据病情给予手术切除联合抗PD-L1等相应治疗,对影响NSCLC患者5年生存率的独立因素进行分析,观察MSI、PD-L1表达对患者5年生存率的影响。结果非小细胞癌组织中MSI表达率为63.95%,明显高于癌旁组织,差异有统计学意义(P<0.05)。PD-L1表达率明显高于癌旁正常组织,差异有统计学意义(P<0.05)。PD-L1表达与肿瘤分化程度、淋巴是否转移、TNM分期有关(P<0.05);MSI状态与肿瘤分化程度、淋巴结转移情况、TNM分期有关(P<0.05)。MSS及MSI-L患者术后生存时间明显低于MSI-H患者,差异有统计学意义(P<0.05)。PD-L1阳性患者术后生存时间明显低于阴性组,差异有统计学意义(P<0.05)。Logistic回归分析显示PD-L1阳性(OR=3.888)、淋巴结转移(OR=3.823)、TNM分期Ⅲ~Ⅳ期(OR=3.380)为影响患者5年生存率独立危险因素,MSI-H阳性为NSCLC患者5年生存率的保护因素(OR=0.289)(P<0.05)。结论 MSI和PD-L1的表达与NSCLC临床病理特征及预后密切相关,可作为NSCLC预后预测的重要指标。     

Companion diagnostic assays for PD-1/PD-L1 checkpoint inhibitors in NSCLC

The immune checkpoint inhibitors pembrolizumab and nivolumab together with their diagnostic assays have recently been granted market authorization for treatment of advanced non-small-cell lung cancer in the USA. The two assays, PD-L1 IHC 22C3 pharmDx and PD-L1 IHC 28-8 pharmDx (both by Dako, Glostrup, Denmark), are the first PD-L1 IHC assays to obtain regulatory approval through the Premarket Approval process. This approval is supported by recent clinical studies that have shown a positive correlation between PD-L1 expression and the outcome following treatment with different PD-1/PD-L1 checkpoint inhibitors. These diagnostic assays are able to identify the group of non-small-cell lung cancer patients who will benefit most from treatment with the immune checkpoint inhibitors. However, so far, it is only the PD-L1 IHC 22C3 pharmDx assay, which is linked to the use of pembrolizumab, that has obtained regulatory status as a companion diagnostic.